Targeted drug delivery in which a bioactive agent (e.g., a drug or a therapeutic) is provided in an active state to a subject's system at effective concentrations is a long sought goal. Many difficulties must be overcome to reach this goal. For instance, a bioactive agent must first be successfully delivered internally, and the human body has developed many barriers to prevent the influx of foreign substances. In addition, the nature of the bioactive agent itself or the concentration of a bioactive agent necessary to obtain the desired effect often leads to formation of a high viscosity composition, which further amplifies the difficulties in successfully passing the body's natural barriers.
Delivery methods presently utilized for high viscosity compositions include oral delivery, injections, and infusions. Unfortunately, these methods all include aspects that are problematic not only with regard to successful delivery of the high viscosity composition, but also for the subject receiving the composition. For instance, injections often utilize small gauge needles that require extremely high pressure over a long period of time for delivery of high viscosity compositions, if they are capable of use for the high viscosity compositions at all. For example, 0.5 milliliter of a 20 centipoise (cP) proteinaceous solution can take up to about 600 seconds for delivery through a 34 gauge needle. In addition, injections are painful particularly when considering the time required for a single dose delivery and, when considering long term use of an agent, can lead to development of scar tissue. Oral delivery requires successful absorption through the epithelial lining of the digestive tract as well as avoidance of break down of the bioactive agent by digestive materials, and both of these hurdles can be extremely difficult to cross. In addition, oral delivery often leads to gastrointestinal distress for the subject. Moreover, both injection and oral delivery tend to provide bursts of agents and wide swings in system concentration rather than a preferred steady-state delivery. Infusion therapy can be used to deliver bioactive agents directly to blood vessels, muscles, or subcutaneous connective tissue. While delivery via infusion therapy now can be carried out on an out-patient basis, or even with long term, relatively steady-state delivery by use of infusion pumps, infusion therapy is invasive, increasing chances for infection at the infusion site, and necessitates the utilization of associated equipment such as pumps, transdermal tubing, etc.
Transdermal delivery devices have been developed in an attempt to provide a painless route for successful delivery of bioactive agents over a sustained period. For instance, transdermal delivery patches have been found useful for providing bioactive agents such as nicotine, scopolamine, estrogen, nitroglycerine, and the like to a subject's system. In order to be successful, a transdermal scheme must deliver an agent across the epidermis, which has evolved with a primary function of keeping foreign substances out. The outermost layer of the epidermis, the stratum corneum, has structural stability provided by overlapping corneocytes and crosslinked keratin fibers held together by coreodesmosomes and embedded within a lipid matrix, all of which provides an excellent barrier function. Beneath the stratum corneum is the stratum granulosum, within which tight junctions are formed between keratinocytes. Tight junctions are barrier structures that include a network of transmembrane proteins embedded in adjacent plasma membranes (e.g., claudins, occludin, and junctional adhesion molecules) as well as multiple plaque proteins (e.g., ZO-1, ZO-2, ZO-3, cingulin, symplekin). Tight junctions are found in internal epithelium and endothelium (e.g., the intestinal epithelium, the blood-brain barrier, blood vessel walls) as well as in the stratum granulosum of the skin. Beneath both the stratum corneum and the stratum granulosum lays the stratum spinosum. The stratum spinosum includes Langerhans cells, which are dendritic cells that may become fully functioning antigen-presenting cells and may institute an immune response and/or a foreign body response to an invading agent.
The addition of microneedles on transdermal delivery devices such as patches has helped to breach initial barriers in the dermis. Unfortunately, even with such improvements, transdermal delivery devices are presently limited to delivery of low viscosity compositions, and in particular low molecular weight agents that have a moderate lipophilicity and no charge. Moreover, even upon successful crossing of the natural boundary, problems still exist with regard to maintaining the activity level of delivered agents and avoidance of foreign body and immune response.
What are needed in the art are devices and methods for delivery of bioactive agents. More specifically, what are needed are devices and methods that can successfully deliver a high viscosity composition that includes a bioactive agent and can also prevent targeting of the bioactive agent by the body's own defensive mechanisms.